Ultrasound Mediated Destruction of LMW-HA-Loaded and Folate-Conjugated Nanobubble for TAM Targeting and Reeducation

Xiao Sun,1 Lu Guo,1 Mengmeng Shang,1 Dandan Shi,1 Ping Liang,2 Xuanxuan Jing,1 Dong Meng,1 Xinxin Liu,1 Xiaoying Zhou,1 Yading Zhao,1 Jie Li1 1Department of Ultrasound, Qilu Hospital of Shandong University, Jinan, People’s Republic of China; 2Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, People’s Republic of ChinaCorrespondence: Jie LiDepartment of Ultrasound, Qilu Hospital of Shandong University, Wenhua Western Road, 107#, Jinan Tel/Fax +86-531-82166101Email jieli301@163.comPurpose: To synthesize and evaluate a novel folate-conjugated ultrasonic nanobubble (HA-FOL-NB) loading low-molecular-weight hyaluronic acid (LMW-HA) for specific tumor-associated macrophages (TAMs) targeting and reeducation.Methods: The characteristics, cytotoxicity, contrast-enhanced ultrasound imaging (CEUS), and targeting ability to TAMs of HA-FOL-NBs were investigated. The TAMs reprogramming function of HA-FOL-NBs combining ultrasound targeted nanobubble destruction was assessed as well.Results: HA-FOL-NBs (about 342nm) showed remarkable contrast enhancement images, and higher targeting ability due to the folate to folate receptor interactions. Combined with ultrasound targeted nanobubble destruction, HA-FOL-NBs could specifically deliver LMW-HA into TAMs, thus exhibited stronger reeducation effect compared with free LMW-HA.Conclusion: These folate-conjugated and LMW-HA-loaded nanobubbles, with targeted CEUS imaging and TAMs reeducation, are expected to be a potential approach for tumor therapy based on TAMs, especially folate receptor-positive ones.Keywords: ultrasound contrast agent, ultrasonic nanobubble, tumor-associated macrophage, tumor microenvironment, contrast-enhanced ultrasound imaging